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Development of a miR-92a delivery system for anti-angiogenesis-based cancer therapy.

AbstractBACKGROUND:
RNA interference has received much attention as a novel therapeutic strategy. MicroRNA (miRNA) appears to be promising as a novel nucleic-acid medicine because it is able to suppress a series of protein expression that relates to a specific event such as angiogenesis. In the present study, we used dicetyl phosphate-tetraethylenepentamine-based polycation liposomes (TEPA-PCL) as a delivery system for miR-92a, one of the miRNAs regulating angiogenesis, and attempted to deliver miR-92a to angiogenic endothelial cells for the development of cancer therapy by anti-angiogenesis.
METHODS:
Cholesterol-grafted miR-92a (miR-92a-C) was bound to TEPA-PCL, and the ratio of nitrogen of TEPA-PCL to phosphorus of miR-92a-C (N/P ratio) was optimized. This complex was transfected into human umbilical vein endothelial cells (HUVECs), and the intracellular localization of miR-92a-C was observed under a confocal laser-scanning microscope by the use of fluorescein isothiocyanate-labeled miR-92a-C. After transfection of HUVECs with miR-92a-C/TEPA-PCL, the expression of miR-92a-target proteins (e.g. integrin α5, mitogen-activated protein kinase kinase 4, sphingosine-1-phosphate receptor 1) was examined by western blotting, and a tube formation assay was performed.
RESULTS:
The complex of miR-92a-C with TEPA-PCL was formed and miR-92a-C remained stable with TEPA-PCL at the N/P ratio of 10. After transfection of HUVECs with miR-92a-C complex, miR-92a-C spread into the whole cytoplasm of the cells without any change of cellular morphology, and the expression of several proteins encoded by miR-92a-target genes was suppressed. Furthermore, the capability of forming capillary tubes was impaired in complex-treated HUVECs.
CONCLUSIONS:
We have developed a miR-92a delivery system into angiogenic endothelial cells by the use of TEPA-PCL. These results suggest that miR-92a-C/TEPA-PCL is promising for the treatment of tumors via the suppression of angiogenesis.
AuthorsHidenori Ando, Ayaka Okamoto, Masafumi Yokota, Kosuke Shimizu, Tomohiro Asai, Takehisa Dewa, Naoto Oku
JournalThe journal of gene medicine (J Gene Med) Vol. 15 Issue 1 Pg. 20-7 (Jan 2013) ISSN: 1521-2254 [Electronic] England
PMID23239404 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 John Wiley & Sons, Ltd.
Chemical References
  • Angiogenesis Inhibitors
  • Ethylenediamines
  • Integrin alpha5
  • Liposomes
  • MIRN92 microRNA, human
  • MicroRNAs
  • Receptors, Lysosphingolipid
  • S1PR1 protein, human
  • Sphingosine-1-Phosphate Receptors
  • MAP Kinase Kinase 4
  • tetraethylenepentamine
Topics
  • Angiogenesis Inhibitors (metabolism)
  • Blotting, Western
  • Cells, Cultured
  • Ethylenediamines (pharmacology)
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Gene Transfer Techniques
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Integrin alpha5 (genetics, metabolism)
  • Liposomes
  • MAP Kinase Kinase 4 (genetics, metabolism)
  • MicroRNAs (genetics, metabolism)
  • Microscopy, Confocal
  • Neoplasms (therapy)
  • Neovascularization, Pathologic (therapy)
  • RNA Interference
  • Receptors, Lysosphingolipid (genetics, metabolism)
  • Sphingosine-1-Phosphate Receptors

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